基于信号分子的有机污染物对微生物Hormesis效应的作用机制及其预测模型研究

Hormesis is a dose?response relationship phenomenon characterized by a low-dose stimulation and a high-dose inhibition. Accumulating evidence has demonstrated that chemical pollutants in environment is low-dose, and therefore hormesis is highly generalizable. However, the mechanistic understanding of hormesis, to date, is extremely limited. In our previous study, it was first reported that, hormesis effect of sulfonamide antibiotics on luminescent bacteria may be highly correlated with quorum sensing (QS), and mechanistic hypothesis of hormesis was proposed by introducing the concept of quorum sensing (QS) at the microbial community level. Based on these previous works, the following studies will include: 1）to further validate mechanistic hypothesis of hormesis on quorum sensing at the microbial community level through the construction of target gene deletion engineering bacteria and the determination of QS; 2) to quantitatively analysis the correlation between hormesis effect and the production of H2O2 and NO, which are key factors in stress signal transduction, to investigate the role of H2O2 and NO in the switch from stimulation to inhibition in dose-response relationship, and to disclose their regulation of hormesis effect at the individual level; 3）to probe the possible cross-talk between NO, H2O2 and QS through the response determination of engineering bacteria before and after the addition of the chemical signal molecules; 4) to predict the hormesis through the QSAR models, which can predict the production of NO, H2O2 and QS based on the chemcial mechanism mentioned above. Therefore, the purpose of our studies is to answer the challenging and urgent question that "which signaling molecules are the key to open the door of the mechanism for hormesis, and how to open ,and how to predict?"

针对环境中污染物大多呈低剂量暴露且普遍具有Hormesis效应，但目前相关机制尚不明确的现状，申请者首次发现磺胺类抗生素对发光菌Hormesis可能与细菌群体感应信号分子（QS）有关，初步阐述了基于QS的Hormesis机制的假设。本申请1）拟在群体水平，进一步通过构建工程菌，验证基于QS的Hormesis机制的假设；2）在个体水平，定量分析位于胁迫信号转导中心环节的H2O2和NO的生成量与Hormesis效应的相关关系，研究它们在化合物的剂量效应关系从刺激到抑制的转变中的作用，揭示它们对Hormesis的调控；3）测定工程菌对外加信号分子的响应，研究NO与H2O2、QS的可能互作（Cross-talk）；4）建立可通过预测污染物作用下各信号分子产生量而估算Hormesis的QSAR模型。旨在回答"哪些化学信号分子才是打开微生物Hormesis机制大门的真正钥匙？如何打开及预测?"这个问题

针对环境中污染物大多呈低剂量暴露且普遍具有Hormesis效应，但目前相关机制尚不明确的现状，申请者1)系统地研究了抗生素对大肠杆菌的hormesis效应产生的条件；2)测定了抗生素在混合碳源体系中对大肠杆菌的hormesis效应，从碳源利用的角度提出了一种hormesis效应的可能机制；3)明晰了ROS和NO在化合物（抗生素和QSIs）对模式生物生物效应中的作用，提出ROS和NO调控的Hormesis效应分子通路和可能互作（Cross-talk）；4)探讨了基于细菌QS信号分子C6和C8的磺胺类抗生素hormesis机制和毒性作用机制，研究它们在化合物的剂量效应关系从刺激到抑制的转变中的作用，揭示它们对Hormesis的调控；5)基于QS的随时间变化，首次揭示了hormesis效应对系列联合作用交叉现象的贡献，并进一步阐明QS系统对交叉现象的重要调控作用，为混合毒性的联合作用研究拓展方向；6) 建立了能预测Hormesis效应的面积法模型和混合化合物的QSAR模型；7)发表了SCI论文23篇（SCI文章总IF为92.356），中文21篇（预计可发表论文20篇(其中SCI刊物14篇以上),或者SCI文章总IF>30），超额完成预期成果。